Int. J. Radiation Oncology Biol. Phys., Vol. 81, No. 5, pp. e721–e726, 2011Copyright � 2011 Elsevier Inc.

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CLINICAL INVESTIGATION Prostate

EFFECT OF WHOLE PELVIC RADIOTHERAPY FOR PATIENTS WITH LOCALLYADVANCED PROSTATE CANCER TREATEDWITH RADIOTHERAPYAND

LONG-TERM ANDROGEN DEPRIVATION THERAPY

GIOVANNA MANTINI, M.D.,* LUCA TAGLIAFERRI, M.D.,* GIAN CARLO MATTIUCCI, M.D.,*MARIO BALDUCCI, M.D.,* VINCENZO FRASCINO, M.D.,* NICOLA DINAPOLI, M.D.,*

CINZIA DI GES�U, M.D.,y EDY IPPOLITO, M.D.,y ALESSIO G. MORGANTI, M.D.,y AND NUMA CELLINI, M.D.*

*Department of Radiotherapy, Policlinico Universitario A. Gemelli, Catholic University, Rome, Italy; yDepartment of Radiotherapy,John Paul II Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy

Reprindel Sacrodiologich8-001685908; E-m

Purpose: To evaluate the effect of whole pelvic radiotherapy (WPRT) in prostate cancer patients treated with RTand long-term (>1 year) androgen deprivation therapy (ADT).Methods and materials: Prostate cancer patients with high-risk features (Stage T3-T4 and/or Gleason score $7and/or prostate-specific antigen level $20 ng/mL) who had undergone RT and long-term ADT were included inthe present analysis. Patients with bowel inflammatory disease, colon diverticula, and colon diverticulitis were ex-cluded from WPRT and treated with prostate-only radiotherapy (PORT). Patients were grouped according tonodal risk involvement as assessed by the Roach formula using different cutoff levels (15%, 20%, 25%, and30%). Biochemical disease-free survival (bDFS) was analyzed in each group according to the RT type (WPRTor PORT).Results: A total of 358 patients treated between 1994 and 2007 were included in the analysis (46.9% with WPRTand 53.1%with PORT). Themedian duration of ADTwas 24months (range, 12–38).With amedian follow-up of 52months (range, 20–150), the overall 4-year bDFS rate was 90.5%. The 4-year bDFS rate was similar between thepatients who had undergoneWPRTor PORT (90.4% vs. 90.5%; p =NS). However, in the group of patients with thegreatest nodal risk (>30%), a significant bDFS improvement was recorded for the patients who had undergoneWPRT (p = .03). No differences were seen in acute toxicity among the patients treated with WPRT or PORT.The late gastrointestinal toxicity was similar in patients treated with PORT or WPRT (p = NS).Conclusions: Our analysis has supported the use of WPRT in association with long-term ADT for patients withhigh-risk nodal involvement (>30%), although a definitive recommendation should be confirmed by a randomizedtrial. � 2011 Elsevier Inc.

Prostate cancer, Prophylactic nodal irradiation, Long-term androgen deprivation therapy.

INTRODUCTION

The role of whole pelvic radiotherapy (WPRT) for prostatecancer patients has continued to be debated. Some studieshave supported pelvic nodal irradiation, reporting improvedoutcomes (1–5). However, some studies, conducted mainlybefore the prostate-specific antigen (PSA) era, did notshow a significant benefit for patients undergoing WPRT(6–10). This negative result was sometimes attributed tothe inclusion in the analysis of low-risk patients (11–15).

Despite the unproved benefit, several randomized studiesevaluating the role of androgen deprivation therapy (ADT)also used WPRT (16–21). Only Radiation TherapyOncology Group (RTOG) 9413 (22) investigated the roleof WPRT in association with ADT. However, that trial inves-

t requests to: Luca Tagliaferri, M.D., Universit�a CattolicaCuore, Roma, Dipartimento di bioimmagini e scienze ra-e, Divisione di Radioterapia, Largo A. Gemelli, RomeItaly. Tel: (+39) 06-3015-4434; Fax: (+39) 06-3015-ail: luca.tagliaferri@rm.unicatt.it

e721

tigated WPRTonly in conjunction with short-term ADT. Norandomized data are available for WPRT in association withlong-term ADT. In particular, the role of WPRT plus long-term ADT for patients with high-risk features has not yetbeen investigated.

Because of these considerations, the aim of the presentanalysis was to retrospectively evaluate the effect ofWPRT for prostate cancer patients treated with RT andlong-term (>1 year) ADT.

METHODS AND MATERIALS

Inclusion criteriaProstate cancer patients with high-risk features (Stage T2c, T3,

or T4 and/or Gleason score of $7 and/or PSA level $20 ng/mL)

Conflict of interest: none.Received May 17, 2010, and in revised form Nov 1, 2010.

Accepted for publication Dec 1, 2010.

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treated with RT and long-term ADT at the Catholic University ofSacred Heart, were included in the present analysis. All the datawere selected from the intranet hospital multidivisional electronicdatabase Spider’s Net (23). The pretreatment evaluation includeda complete medical history, digital rectal examination, completeblood cell count, biochemistry analysis, PSA and testosterone se-rum determination, chest radiography, computed tomography ormagnetic resonance imaging of the abdomen and pelvis, andbone scanning.

RadiotherapyAccording to internal guidelines, the patients with clinical Stage

T2c, T3, or T4 and/or Gleason score of $7, and/or PSA level of$20 ng/mL were candidates for WPRT. The comorbidities of pa-tients were evaluated clinically and instrumental examinations. Pa-tients with a risk of gastrointestinal toxicity that was too greatunderwent prostate-only RT (PORT). The exclusion criteria in-cluded bowel inflammatory disease, colon diverticula, and colon di-verticulitis. The patients who had undergone WPRT wereimmobilized in the prone position, using the up-down table (24)to reduce small bowel irradiation. The patients treated by PORTwere immobilized in the supine position. From January 2000 on-ward, three-dimensional conformal RT was used. Until 1999, fieldmargins were defined using bony landmarks. Larger fields were de-signed to cover the pelvic nodes. The superior margin was 1-1.5 cmabove the promontorium and the inferior margin at the bottom ofthe ischial tuberosities. The lateral margins of the anterior/ poste-rior portals were at 1.5-2 cm from the lateral bony pelvis. The an-terior margin of the lateral portals was anterior to the pubicsymphysis. Posteriorly, the portals included the presacral lymph no-des above S3.Fields size was reduced to 10 x 11 cm or 12 x 14 cmaccording to disease clinical stage, to boost the prostate and seminalvesicles region. For patients treated with three-dimensional confor-mal RT, the first clinical target volume was the prostate as definedusing computed tomography and/or magnetic resonance imaging.The second CTV was the first CTV plus seminal vesicles. The thirdCTV was the second CTV plus the pelvic nodes (i.e., presacral, ob-turator, internal iliac, and external iliac chains). The first planningtarget volume (PTV), second PTV, and third PTV were definedby adding a 1-cm margin to the corresponding CTVs. Patientstreated with PORT were irradiated only to first and second PTVs.RT was delivered using 10-MV photons and a four-field isocentrictechnique for pelvic nodal irradiation and a box technique (two-di-mensional) or a six-field isocentric technique (three-dimensional)for prostate and seminal vesicle irradiation. The pelvic nodes re-ceived 45 Gy in 25 fractions delivered within 5 weeks. The seminalvesicles received 55.8 Gy (for Stage T1-T3a) or 64.8 Gy (for StageT3b-T4) according to the clinical stage. The total dose to the pros-tate and involved seminal vesicles was 70.2 Gy for patients treateduntil 1999 and 73.8 Gy for patients treated afterward. The radiationdose was prescribed at the isocenter according to the InternationalCommission on Radiation Units and Measurements Reports 50 and62 (25, 26).

Androgen deprivation therapyAccording to our guidelines, neoadjuvant, concomitant, and ad-

juvant ADT was prescribed to patients with clinical Stage T3-T4and/or a Gleason score >7 and/or a PSA level >20 ng/mL. TheADT protocol was neoadjuvant for 2 months before RT; concomi-tant (ie, during RT); or long-term ADT (for$1 year). A luteinizinghormone-releasing hormone agonist (1 vial of Goserelin every 28days) was prescribed. Antiandrogen therapy (flutamide before

1996 and bicalutamide 50 mg thereafter) was administered 15days before starting luteinizing hormone-releasing hormone ago-nist therapy and continued for 1 month to avoid the testosteroneflare.

Evaluation criteriaThe disease stage was classified using the American Joint Com-

mittee on Cancer TNM staging system, 2002 edition (27). Patientstreated before 2002 underwent repeat disease staging according tothis latter system. The risk of nodal involvement was assessed usingthe Roach formula (15). Patients were evaluated at 6–7 weeks afterthe end of RT and then every 6 months. Acute toxicity was evalu-ated according to the RTOG scale (28) and late toxicity accordingto the RTOG-European Organization for Research and Treatmentof Cancer scale (29). Biochemical failure was defined as a PSAlevel >1.0 ng/mL during follow-up (30). For each patient, biochem-ical disease-free survival (bDFS) was calculated from the begin-ning of neoadjuvant ADT to biochemical failure. The stagingdata, PSA value at diagnosis, Gleason score, treatment data, andfollow-up data were stored in our multidivisional electronic data-base.

Statistical analysisThe primary endpoint of the analysis was to retrospectively eval-

uate the effect ofWPRTon bDFS in patients who had undergone RTand long-term ADT. The bDFS data were analyzed using theKaplan-Meier method (31). A subgroup analysis was performed,grouping patients according to the nodal risk involvement, as as-sessed by the Roach formula (15) using different cutoff levels(15%, 20%, 25%, and 30%). Furthermore, the following variableswere tested in correlation with the bDFS: treatment type (e.g.,WPRT, PORT), prostate radiation dose, ADT duration, PSA valueat diagnosis, and total Gleason score. A comparison of the survivalcurves was performed using log–rank analysis (32). A Cox propor-tional hazards regression model was applied for multivariate anal-ysis (33). The secondary endpoint was to evaluate the acute and latetoxicity related toWPRT. Freedom from any Grade 2 or greater latetoxicity was analyzed using the Kaplan-Meier method (31). Thestatistical analysis was performed using Systat, version 11 (SPSSScience, Chicago, IL).

RESULTS

Patient characteristicsFrom the data stored in Spider’s Net for 957 prostate can-

cer patients, we identified 358 high-risk patients who had un-dergone external beam RT combined with long-term ADTbetween 1994 and 2007. Of the 358 patients, 33 had under-gone treatment before 1999 with two-dimensional treatmentplanning and 325 had undergone treatment after January2000 with three-dimensional treatment planning.

Of the 358 patients, 168 (46.9%) were treated with WPRTand 190 (53.1%) with PORT. Their median age was 71 years(range, 42–83). The median duration of ADTwas 24 months(range, 12–38). The patient characteristics are listed inTable 1. No significant differences were found between thepatients treated with PORT or WPRT, including diseasestage, Gleason score, or PSA level at diagnosis.

The patients were stratified according to nodal involve-ment risk (Table 2). In the risk groups, the distribution

Table 1. Patient characteristics

Characteristic Total WPRT PORT p

Patients (n) 358 168 190Age (y)Median 71 70 71Range 42–83 42–80 56–83

Stage .29T1–T2a 37 (10.3) 20 (12.0) 17 (9.0)T2bc–T3a 238 (66.4) 112 (66.6) 126 (66.3)T3b 83 (23.3) 36 (21.4) 47 (24.7)

PSA level (ng/mL) .17<10 161 (45.0) 69 (41.1) 92 (48.4)10–20 115 (32.1) 57 (33.9) 58 (30.5)>20 82 (22.9) 42 (25.0) 40 (21.1)

Gleason score .842–6 159 (44.4) 76 (45.3) 83 (43.7)7 135 (37.7) 62 (36.9) 73 (38.4)8–10 64 (17.9) 30 (17.8) 34 (17.9)

Abbreviations: WPRT = whole pelvic radiotherapy; PORT =prostate-only radiotherapy; PSA = prostate-specific antigen.Data in parentheses are percentages.

Fig. 1. Kaplan-Meier estimates of biochemical disease-free sur-vival stratified by treatment (whole pelvic radiotherapy [WPRT]vs. prostate-only radiotherapy [PORT]).

WPRT, PNI, and long-term ADT for high-risk prostate cancer d G. MANTINI et al. e723

between patients in theWPRTand PORT group was uniform(risk >15, p = .3; risk >20, p = .5; risk >25, p = .7; risk >30,p = .6).

EfficacyWith a median follow-up of 52 months (range, 20–150),

the 4-year bDFS rate for the whole patient population was90.5%. The overall 4-year bDFS rate (Fig. 1) was similar be-tween WPRT and PORT groups (90.4% vs. 90.5%; p = NS).The bDFS rates obtained for the different groups are summa-rized in Table 2. In each nodal risk group, the bDFS was cal-culated according to the treatment group (WPRT or PORT;Fig. 2). The 4-year bDFS rate was prolonged in patientswith the greatest risk of nodal involvement (>30%) whohad undergone underwent WPRT (87.9% vs. 70.4%; p =.03). This result was confirmed on multivariate analysis(p = .03). Also, the patients with a nodal risk involvement

Table 2. Four-year bDFS rates stratified by nodal riskinvolvement and treatment

Nodal risk*involvement

cutoffs TreatmentPatients(n)

4-y bDFS rate

(%)

p

Univariateanalysis

Multivariateanalysis

>15 PORT 95 84.3 .80 .6WPRT 82 88.0

>20 PORT 67 76.0 .29 .22WPRT 60 89.5

>25 PORT 50 69.0 .07 .09WPRT 47 86.8

>30 PORT 38 70.4 .03y .03y

WPRT 34 87.9

Abbreviations: bDFS = biochemical disease-free survival; otherabbreviations as in Table 1.* Calculated using Roach formula.y Statistically significant.

>25% who had undergone WPRT showed 4-year bDFS im-provement, reaching a trend toward statistical significance(86.8% vs. 69.0%; p = .07).

ToxicityGrade 3 acute toxicity, either gastrointestinal (GI) or gen-

itourinary (GU), was mild (2.4% and 3.5%, respectively).No Grade 4 acute toxicity was reported. The overall inci-dence of GI and GU acute Grade 2 or greater toxicity wassimilar for the patients treated with PORT or WPRT (GI,10.2% vs. 9.9%, p = NS; GU, 15.2% vs. 11.6%, p = NS).Acute toxicity is detailed in Table 3. The 4-year freedomfrom Grade 2 or greater GU late toxicity rate was 58% forpatients treated with PORT and 55% for patients treatedwith WPRT (p = NS). The 4-year freedom from Grade 2or greater GI late toxicity rate was similar for the patientstreated with PORT or WPRT (49.6% vs. 53.2%, p = NS).

DISCUSSION

In the radical treatment of prostate cancer, the risk of pelvicnodal metastasis has usually been assessed using normogramsand equations (12–14) derived from data from standardsurgical lymphadenectomy. However, several studies haveshown that extended pelvic lymphadenectomy, whichremoves not only the external iliac and obturator nodeschains, but also the hypogastric, internal iliac, and presacralnode chains, has been associated with a greater incidence ofnodal metastasis (34, 35). Hence, the risk of nodalmetastasis using normograms and equations might beunderestimated.

Pelvic nodal RT, sterilizing occult nodal metastases,would improve disease-free survival and overall survival inpatients with an increased risk of nodal involvement(36, 37). However, the published data available on the

Fig. 2. Kaplan-Meier estimates of biochemical disease-free survival stratified by different nodal risk involvement andtreatment (whole pelvic radiotherapy [WPRT] vs. prosate-only radiotherapy [PORT]).

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potential benefits of pelvic nodal RT for prostate cancerpatients have been controversial, especially whenassociated with long-term ADT.

We conducted the present analysis to evaluate the effect ofWPRT for prostate cancer patients treated with RTand long-term (>1 year) ADT. The major limitation of our study wasrelated to the retrospective analysis. Other drawbacks in-cluded the restricted number of patients analyzed (n =

Table 3. Acute toxicity

Grade

Acute toxicity (%)

Skin GI GU

PORT WPRT PORT WPRT PORT WPRT

0 40.7 35.1 22 17 12.8 11.41 7.2 6.7 20.1 18.9 24.3 23.42 3.3 3.3 9.4 8.3 13.6 9.73 0.8 0.2 0.8 1.6 1.6 1.94 0 0 0 0 0 0

Abbreviations: GI = gastrointestinal; GU = genitourinary; otherabbreviations as in Table 1.

378), especially regarding the subgroup analysis, the limitedfollow-up period (median, 52 months), and the dissimilardose delivered and techniques used during the differenttreatment periods. In addition, we defined biochemical fail-ure as the finding of a post-RT PSA level >1.0 ng/mL, whichdoes not correspond to the latest American Society for Radi-ology Oncology definition (38). However, the value we usedwas introduced by Perez et al. (30), who demonstrateda close correlation in terms of bDFS using the primaryAmerican Society for Radiology Oncology Consensus defi-nition (3 consecutive increases in PSA level $3 monthsapart) (39) and the elevation of a post-RT PSA level >1ng/mL.

In our series, the overall 4-year bDFS rate was similar forthe patients treated with WPRT or PORT. The long-termADT probably contributed to prolong the bDFS in the pa-tients with a greater risk of nodal involvement who under-went PORT. In the subset analysis of patients witha different risk of nodal involvement, we also performedmultivariate analysis, trying to account for all the confound-ing factors. The results obtained were consistent with thosefrom the univariate analysis (Table 2). The 4-year bDFS ratewas significantly prolonged in the patients with the greatest

WPRT, PNI, and long-term ADT for high-risk prostate cancer d G. MANTINI et al. e725

nodal risk (>30%) who had undergone WPRT comparedwith those who had undergone PORT (87.9% vs. 70.4%;p = .03). This result was confirmed on multivariate analysis(p = .03). Also, the patients with a risk of nodal involvement>25% who had undergone WPRT had a prolonged 4-yearbDFS rate compared with those who had undergone PORT(86.8% vs. 69%, respectively), although the difference wasnot statistically significant (p = .07). These latter resultscould have been influenced by the limited follow-up period(median, 52 months) and the small number of patients ana-lyzed in each group.

A similar study was recently published by Aizer et al.(40). Their retrospective analysis included the data from>277 patients to determine whether WPRTor PORTyieldedimproved bDFS in patients with at least a 15% risk of nodalinvolvement according to the Roach formula. They found nostatistically significant difference in bDFS between thePORT and WPRT groups (p = .38), as indicated by thelog–rank test. However, the multivariate analysis indicatedthat WPRT was related to improved outcomes comparedwith PORT (p = .006).

The RTOG 94-13 trial (22) was designed to compareWPRT and PORT, as well as neoadjuvant and concurrentADT (NADT) vs. adjuvant ADT in patients with a risk oflymph node involvement of >15%. Between 1995 and1999, 1,323 patients were randomized to WPRT plusNADT, WPRT plus adjuvant ADT, PORT plus NADT, andPORT plus adjuvant ADT. With a median follow-up of59.5 months, WPRT was associated with a 4-yearprogression-free survival rate of 54% compared with 47%for PORT (p = .022). Comparing all four arms, theprogression-free survival was greater for the patients whohad undergone WPRT plus NADT (p =.008). From thesedata, the investigators concluded that when NADT wasused in conjunction with RT for patients with a likelihood

of nodal involvement >15%, WPRT yielded betterprogression-free survival than PORT.

Despite the similarities2 of these studies with our study,our analysis has provided some novel information. First,compared with the retrospective analysis conducted by Ai-zer et al. (40), the patients undergoing WPRT had diseaseat baseline that was similar to that of the patients undergoingPORT, and were all treated with long-term ADT. Second, inanalyzing the bDFS in the different patient groups accordingto nodal risk involvement, our study demonstrated thatWPRT achieved improved bDFS when associated withlong-term ADT in the patients presenting with the greatestrisk of nodal involvement (>30%).

The acute and late toxicity rates reported in patientstreated with WPRT were acceptable. The acute toxicitywas similar between WPRT and PORT groups. This resultmight appear in contrast to those from several studies report-ing greater rates of acute toxicity for patients undergoingWPRT (41, 42). However, the reported rate of toxicityfrom our analysis can be explained by the exclusion fromWPRT of patients with previous comorbidities and by theuse of the up-down table and prone position for patients un-dergoing WPRT. The 4-year freedom from Grade 2 orgreater late GI toxicity rate was similar for the two groups(53.2% vs. 49.6%; p = NS), although longer follow-up isneeded to confirm these results. These latter data might beconsistent with the data on acute toxicity, supporting themain role of GI comorbidities as predictors of GI toxicity.

CONCLUSIONS

With a median follow-up of 52 months (range, 20–150),our analysis supports the use of WPRT in association withlong-term ADT for patients with a high risk of nodal in-volvement (>30%), although a definitive recommendationmust be confirmed by a randomized trial.

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